Hippocampal neuronal subpopulations are differentially affected in double transgenic mice overexpressing frontotemporal dementia and parkinsonism linked to chromosome 17 tau and glycogen synthase kinase-3beta.
Glycogen synthase kinase-3beta (GSK-3beta) has been proposed as the main kinase able to phosphorylate tau aberrantly in Alzheimer's disease and in related tauopathies. We have previously generated a double transgenic mouse line overexpressing the enzyme GSK-3beta and tau protein carrying a triple frontotemporal dementia and parkinsonism linked to chromosome 17 mutation whose expression patterns overlap in CA1 (pyramidal neurons) and dentate gyrus (granular neurons). Here, we have used this transgenic model to analyze how axonal and somatodendritic neuronal compartments are affected in the hippocampus. Our data demonstrate that neuronal subpopulations respond differentially to increased GSK-3 activity. Thus, dentate gyrus granular neurons undergo apoptotic death with subsequent degeneration of the mossy fibers, while CA1 pyramidal neurons accumulate hyperphosphorylated tau both in the axonal and in the somatodendritic compartments. These studies also allow us to propose a model of spreading of pathology through the hippocampus as a consequence of GSK-3 and tau dysregulation.
Engel
T
T
Centro de Biología Molecular "Severo Ochoa," CSIC/UAM, Fac. Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Goñi-Oliver
P
P
Gomez-Ramos
P
P
Morán
M A
MA
Lucas
J J
JJ
Avila
J
J
Hernández
F
F
D000367:Age Factors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D007211:Indoles; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000145:classification* / Q000502:physiology* / Q000648:ultrastructure; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; C085349:PHF-1 monoclonal antibody; D016875:tau Proteins; C007293:DAPI; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3